Several FDA-approved drug labels may be available for Odefsey. AIDSinfo provides the following drug label solely as an example of the labels available for Odefsey. Inclusion or absence of a drug label on the AIDSinfo site does not imply endorsement or lack thereof by AIDSinfo. Search Drugs@FDA to access more information on Odefsey, including additional drug labels and any generic equivalents.

ODEFSEY is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of ODEFSEY. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted. (5.1)

INDICATIONS AND USAGE

ODEFSEY is a three-drug combination of emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV nucleoside analog reverse transcriptase inhibitors (NRTIs), and rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), and is indicated as a complete regimen for the treatment of HIV-1 infection in patients 12 years of age and older as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies per mL; or to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of ODEFSEY. (1)

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

ODEFSEY is contraindicated when coadministered with drugs where significant decreases in RPV plasma concentrations may occur, which may result in loss of virologic response and possible resistance and cross-resistance. (4)

WARNINGS AND PRECAUTIONS

Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during postmarketing experience with RPV-containing regimens, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develops and closely monitor clinical status, including hepatic serum biochemistries. (5.2)

Concomitant use of ODEFSEY with other drugs that may reduce the exposure of RPV may lead to loss of therapeutic effect of ODEFSEY and possible development of resistance. (5.3)

Concomitant use of ODEFSEY with drugs with a known risk to prolong the QTc interval of the electrocardiogram may increase the risk of Torsade de Pointes. (5.4)

Hepatotoxicity: Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Monitor liver-associated tests before and during treatment with ODEFSEY in patients with underlying hepatic disease or marked elevations in liver-associated tests. Also consider monitoring liver-associated tests in patients without risk factors. (5.6)

Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.7)

USE IN SPECIFIC POPULATIONS

Lactation: Women infected with HIV should be instructed not to breastfeed, due to the potential for HIV transmission. (8.2)

Pediatrics: Not recommended for patients less than 12 years of age or weighing less than 35 kg. (8.4)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised: 08/2017

FULL PRESCRIBING INFORMATION

WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

ODEFSEY is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of ODEFSEY have not been established in patients coinfected with human immunodeficiency virus-1 (HIV-1) and HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of ODEFSEY.

Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue ODEFSEY. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

ODEFSEY is indicated as a complete regimen for the treatment of HIV-1 infection in patients 12 years of age and older as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies per mL; or to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of ODEFSEY [see Microbiology (12.4) and Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Testing Prior to Initiation of ODEFSEY

It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein should be assessed before initiating ODEFSEY and during therapy in all patients as clinically appropriate [see Warnings and Precautions (5.8)].

2.2 Recommended Dosage

ODEFSEY is a 3-drug fixed dose combination product containing 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV), and 25 mg of tenofovir alafenamide (TAF). The recommended dosage of ODEFSEY is one tablet taken orally once daily with a meal in the following patient population: adults and in pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg and a creatinine clearance greater than or equal to 30 mL per minute [see Clinical Pharmacology (12.3)].

5 WARNINGS AND PRECAUTIONS

Patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy [see Dosage and Administration (2.1)]. ODEFSEY is not approved for the treatment of chronic HBV infection, and the safety and efficacy of ODEFSEY have not been established in patients coinfected with HIV-1 and HBV.

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing FTC and/or TDF, and may occur with discontinuation of ODEFSEY. Patients coinfected with HIV-1 and HBV who discontinue ODEFSEY should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of antihepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2 Skin and Hypersensitivity Reactions

Severe skin and hypersensitivity reactions, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during postmarketing experience with RPV-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunction, including elevations in hepatic serum biochemistries. During Phase 3 clinical trials of RPV, treatment-related rashes with at least Grade 2 severity were reported in 1% of subjects. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [see Adverse Reactions (6.2)].

Discontinue ODEFSEY immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated.

5.3 Loss of Virologic Response Due to Drug Interactions

The concomitant use of ODEFSEY and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of ODEFSEY and possible development of resistance due to reduced exposure of RPV.

See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Contraindications (4) and Drug Interactions (7)]. Consider the potential for drug interactions prior to and during ODEFSEY therapy; review concomitant medications during ODEFSEY therapy; and monitor for the adverse reactions associated with the concomitant drugs.

5.4 Prolongation of QTc Interval with Higher Than Recommended Dosages

In healthy subjects, higher than recommended doses of RPV (75 mg once daily and 300 mg once daily – 3 and 12 times the recommended dosages, respectively) have been shown to prolong the QTc interval of the electrocardiogram [see Drug Interactions (7.2) and Clinical Pharmacology (12.2)]. Consider alternatives to ODEFSEY when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsades de Pointes.

5.5 Depressive Disorders

Depressive disorders (including depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with RPV. Promptly evaluate patients with severe depressive symptoms to assess whether the symptoms are related to ODEFSEY, and to determine whether the risks of continued therapy outweigh the benefits.

In Phase 3 trials of RPV in adult subjects (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among RPV-treated subjects (n=686) was 9%. Most events were mild or moderate in severity. In RPV-treated subjects, the incidence of Grades 3 and 4 depressive disorders (regardless of causality) was 1%, the incidence of discontinuation due to depressive disorders was 1%, and suicidal ideation and suicide attempt was reported in 4 and 2 subjects, respectively.

During the Phase 2 trial in RPV-treated pediatric subjects 12 to less than 18 years of age (N=36), the incidence of depressive disorders (regardless of causality, severity) was 19% (7/36) through 48 weeks. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject.

5.6 Hepatotoxicity

Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Patients with underlying hepatitis B or C, or marked elevations in liver-associated tests prior to treatment, may be at increased risk for worsening or development of liver-associated test elevations with use of ODEFSEY. A few cases of hepatic toxicity have been reported in adult patients receiving a RPV-containing regimen who had no preexisting hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with ODEFSEY is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in liver-associated tests prior to treatment initiation. Liver-associated test monitoring should also be considered for patients without preexisting hepatic dysfunction or other risk factors.

5.7 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including FTC and RPV, both components of ODEFSEY. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.8 New Onset or Worsening Renal Impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of FTC+TAF with EVG+COBI, there have been no cases of Fanconi syndrome or proximal renal tubulopathy (PRT). In clinical trials of FTC+TAF with EVG+COBI in treatment-naïve subjects and in virologically-suppressed subjects switched to FTC+TAF with EVG+COBI with eGFRs greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with FTC+TAF with EVG+COBI. In a study of virologically-suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with FTC+TAF with EVG+COBI for a median duration of 43 weeks, FTC+TAF with EVG+COBI was permanently discontinued due to worsening renal function in two of 80 (3%) subjects with a baseline eGFR between 30 and 50 mL per minute [see Adverse Reactions (6.1)]. ODEFSEY is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population are insufficient.

It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose and urine protein be assessed before initiating ODEFSEY therapy and during therapy in all patients as clinically appropriate. Discontinue ODEFSEY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

5.9 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of ODEFSEY, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with ODEFSEY should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

6 ADVERSE REACTIONS

The following adverse reactions are discussed in other sections of the labeling:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug (or a drug given in various combinations with other concomitant therapy) cannot be directly compared to rates in the clinical trials of another drug (or drug given in the same or different combination therapy) and may not reflect the rates observed in practice.

The safety of ODEFSEY in virologically-suppressed adults is based on Week 48 data from two randomized, double-blinded, active-controlled clinical trials, 1160 and 1216, that enrolled 1505 adult subjects who were virologically-suppressed for at least 6 months. Both trials were designed to compare switching to ODEFSEY to maintaining efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) or emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) in Trials 1160 and 1216, respectively. A total of 754 subjects received one tablet of ODEFSEY daily [see Clinical Studies (14.1)].

The most common adverse reactions (all Grades) reported in at least 2% of subjects in the ODEFSEY group across Trials 1216 and 1160 were headache and sleep disturbances (Table 1). Over 98% of the adverse reactions in the ODEFSEY group were of mild to moderate intensity. The proportion of subjects who discontinued treatment with ODEFSEY due to adverse events, regardless of severity, was 2% compared to 1% for FTC/RPV/TDF and 2% for EFV/FTC/TDF.

Data from Trials 1160 and 1216 do not provide an adequate basis for comparison of adverse reaction incidences between ODEFSEY and the FTC/RPV/TDF and EFV/FTC/TDF groups.

Headache

2%

1%

0

1%

Flatulence

1%

<1%

<1%

1%

Sleep Disturbances

2%

1%

0

<1%

Abnormal Dreams

1%

1%

0

2%

Diarrhea

1%

3%

1%

2%

Nausea

1%

1%

1%

1%

Renal Laboratory Tests

In Trial 1216, the median baseline eGFR was104 mL per minute for subjects who switched to ODEFSEY from FTC/RPV/TDF (N=316) and the mean serum creatinine decreased by 0.02 mg per dL from baseline to Week 48.

In Trial 1160, the median baseline eGFR was 110 mL per minute for subjects who switched to ODEFSEY from EFV/FTC/TDF (N=438), and the mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48.

Bone Mineral Density Effects

Changes in BMD from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA) in Trials 1216 and 1160.

In Trial 1216, mean bone mineral density (BMD) increased in subjects who switched to ODEFSEY (1.61% lumbar spine, 1.04% total hip) and remained stable or decreased in subjects who remained on FTC/RPV/TDF (0.08% lumbar spine, –0.25% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1.7% of ODEFSEY subjects and 3.0% of FTC/RPV/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 0% of ODEFSEY subjects and 1.2% of FTC/RPV/TDF subjects.

In Trial 1160, mean BMD increased in subjects who switched to ODEFSEY (1.65% lumbar spine, 1.28% total hip) and decreased slightly in subjects who remained on EFV/FTC/TDF (–0.05% lumbar spine, –0.13% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 2.3% of ODEFSEY subjects and 4.9% of EFV/FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 1.4% of ODEFSEY subjects and 3.3% of EFV/FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known.

Serum Lipids

Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio for Trials 1216 and 1160 are presented in Table 2.

In pooled 96-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects, the most common adverse reactions in subjects treated with RPV+FTC/TDF (N=550) (incidence greater than or equal to 2%, Grades 2−4) were headache, depressive disorders, and insomnia. The proportion of subjects who discontinued treatment with RPV+FTC/TDF due to adverse reactions, regardless of severity, was 2%. The most common adverse reactions that led to discontinuation in this treatment group were psychiatric disorders (1.6%) and rash (0.2%). Although the safety profile was similar in virologically-suppressed adults with HIV-1 infection who were switched to RPV and other antiretroviral drugs, the frequency of adverse events increased by 20% (N=317).

Adverse Reactions in Clinical Trials of FTC+TAF with EVG+COBI in Treatment-Naïve Adult Subjects with HIV-1 Infection

In pooled 48-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects, the most common adverse reaction in subjects treated with FTC+TAF with EVG+COBI (N=866) (incidence greater than or equal to 10%, all grades) was nausea (10%). In this treatment group, 0.9% of subjects discontinued FTC+TAF with EVG+COBI due to adverse event [see Clinical Studies (14)]. Antiretroviral treatment-naïve adult subjects treated with FTC+TAF with EVG+COBI experienced mean increases of 30 mg/dL of total cholesterol, 15 mg/dL of LDL cholesterol, 7 mg/dL of HDL cholesterol and 29 mg/dL of triglycerides after 48 weeks of use.

Renal Laboratory Tests

In two 48-week trials in antiretroviral treatment-naïve HIV-1 infected adults treated with FTC+TAF with EVG+COBI (N=866) with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. In a 24-week trial in adults with renal impairment (baseline eGFR 30 to 69 mL per minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5 mg per dL at both baseline and Week 24.

Bone Mineral Density Effects

In the pooled analysis of two 48-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects, bone mineral density (BMD) from baseline to Week 48 was assessed by dual-energy X-ray absorptiometry (DXA). Mean BMD decreased from baseline to Week 48 by −1.30% with FTC+TAF with EVG+COBI at the lumbar spine and -0.66% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 10% of FTC+TAF with EVG+COBI subjects. BMD declines of 7% or greater at the femoral neck were experienced by 7% of FTC+TAF with EVG+COBI subjects. The long-term clinical significance of these BMD changes is not known.

In an open-label 48-week trial of 36 antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years old (weighing at least 32 kg) treated with 25 mg per day of RPV and other antiretrovirals, the most common adverse reactions were headache (19%), depression (19%), somnolence (14%), nausea (11%), dizziness (8%), abdominal pain (8%), vomiting (6%) and rash (6%).

In a 24-week, open-label trial of 23 antiretroviral treatment-naïve HIV-1 infected pediatric subjects aged 12 to less than 18 years old (weighing at least 35 kg) who received FTC+TAF with EVG+COBI, the safety of this combination was similar to that of adults. Among these pediatric subjects, mean BMD increased from baseline to Week 24, +1.7% at the lumbar spine and +0.8% for the total body less head. Mean changes from baseline BMD Z-scores were -0.10 for lumbar spine and -0.11 for total body less head at Week 24. Two subjects had significant (greater than 4%) lumbar spine BMD loss at Week 24.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing experience in patients receiving RPV-containing regimens. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7 DRUG INTERACTIONS

7.1 Potential for Other Drugs to Affect One or More Components of ODEFSEY

Drugs that Induce or Inhibit CYP3A Enzymes

RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of RPV [see Clinical Pharmacology (12.3)]. Coadministration of RPV and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs [see Contraindications (4), Warnings and Precautions (5.3), and Table 3]. These drugs are contraindicated and include:

Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV and possible adverse events.

Drugs that Induce or Inhibit P-glycoprotein

TAF, a component of ODEFSEY, is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp and BCRP activity may lead to changes in TAF absorption (see Table 3). Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of ODEFSEY and development of resistance. Coadministration of ODEFSEY with other drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentration of TAF.

Drugs that Increase Gastric pH

Coadministration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and lead to loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Use of RPV with proton pump inhibitors is contraindicated and use of RPV with H2-receptor antagonists requires staggered administration (see see Contraindications (4) and Table 3).

7.2 QT Prolonging Drugs

There is limited information available on the potential for a pharmacodynamic interaction between RPV and drugs that prolong the QTc interval. In a study of healthy subjects, higher than recommended doses of RPV, 75 mg once daily and 300 mg once daily (3 times and 12 times recommended daily dose in ODEFSEY) prolonged the QTc interval [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.2)]. Consider alternative medications to ODEFSEY in patients taking a drug with a known risk of Torsade de Pointes.

7.3 Drugs that Affect Renal Function

Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of ODEFSEY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.8)].

7.4 Established and Other Potentially Significant Drug Interactions

Table 3 provides a listing of established or potentially clinically significant drug interactions with recommended steps to prevent or manage the drug interaction (the table is not all inclusive). The drug interactions described are based on studies conducted with either ODEFSEY, the components of ODEFSEY (FTC, RPV and TAF) as individual agents, or are predicted drug interactions that may occur with ODEFSEY. For pharmacokinetic data, see Tables 7–10 [see Clinical Pharmacology (12.3)].

Table 3 Established and Other Potentially Significant* Drug Interactions

No dosage adjustment is required when ODEFSEY is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with ODEFSEY.

H2-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine

↔ RPV‡,§(famotidine taken 12 hours before RPV or 4 hours after RPV)↓ RPV‡,§(famotidine taken 2 hours before RPV)

Administer H2-receptor antagonists at least 12 hours before or at least 4 hours after ODEFSEY.

No dosage adjustments are required when initiating coadministration of methadone with ODEFSEY. However, clinical monitoring is recommended, as methadone maintenance therapy may need to be adjusted in some patients.

7.5 Drugs Without Clinically Significant Interactions with ODEFSEY

Based on drug interaction studies conducted with the fixed dose combination or components of ODEFSEY, no clinically significant drug interactions have been either observed or expected when ODEFSEY is combined with the following drugs: acetaminophen, atorvastatin, buprenorphine, chlorzoxazone, digoxin, ethinyl estradiol, ledipasvir, lorazepam, metformin, midazolam, naloxone, norbuprenorphine, norethindrone, norgestimate/ethinyl estradiol, sildenafil, simeprevir, sofosbuvir, and velpatasvir.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ODEFSEY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

There are insufficient human data on the use of ODEFSEY during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Tenofovir alafenamide (TAF) use in women during pregnancy have not been evaluated; however, emtricitabine (FTC) and rilpivirine (RPV) use during pregnancy has been evaluated in a limited number of women reported to the APR. Available data from the APR show no difference in the risk of overall major birth defects for FTC and RPV compared with the background rate for major birth defects of 2.7% in a US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15–20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.

In animal studies, no adverse developmental effects were observed when the components of ODEFSEY were administered separately during the period of organogenesis at exposures up to 60 and 108 times (mice and rabbits, respectively; FTC), 15 and 70 times (rats and rabbits, respectively; RPV) and equal to and 53 times (rats and rabbits, respectively; TAF) the exposure at the recommended daily dose of these components in ODEFSEY [see Data (8.1)]. Likewise, no adverse developmental effects were seen when FTC was administered to mice and RPV was administered to rats through lactation at exposures up to approximately 60 and 63 times, respectively, the exposure at the recommended daily dose of these components in ODEFSEY. No adverse effects were observed in the offspring when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of ODEFSEY.

Data

Human Data

Emtricitabine: Based on prospective reports to the APR of 3406 exposures to FTC-containing regimens during pregnancy (including 2326 exposed in the first trimester and 1080 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7% to 3.0%) with first trimester exposure to FTC-containing regimens and 2.0% (95% CI: 1.3% to 3.1%) with second/third trimester exposure to FTC-containing regimens.

Rilpivirine: Based on prospective reports to the APR of 326 live births following exposures to RPV-containing regimens during pregnancy (including 202 exposed in the first trimester and 124 exposed in the second/third trimester), there was no difference in the rate of overall birth defects for RPV compared with the background rate of 2.7% for major birth defects in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 0.5% (95% CI: 0.0% to 2.7%) with first trimester exposure to RPV-containing regimens and 0.8% (95% CI: 0.0% to 4.4%) with second/third trimester exposure to RPV-containing regimens.

Animal Data

Emtricitabine: FTC was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study with FTC, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended daily dose.

Rilpivirine: RPV was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with RPV in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose of 25 mg once daily. In a pre/postnatal development study with RPV, where rats were administered up to 400 mg/kg/day through lactation, no significant adverse effects directly related to drug were noted in the offspring.

Tenofovir Alafenamide: TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures similar to (rats) and approximately 53 (rabbits) times higher than the exposure in humans at the recommended daily dose of ODEFSEY. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 59 (rats) and 93 (rabbits) times higher than human tenofovir exposures at the recommended daily doses. Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to tenofovir disoproxil fumarate (TDF, another prodrug for tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation, no adverse effects were observed in the offspring on gestation day 7 [and lactation day 20] at tenofovir exposures of approximately 14 [21] times higher than the exposures in humans at the recommended daily dose of ODEFSEY.

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV.

Based on published data, FTC has been shown to be present in human breast milk; it is unknown if RPV and TAF are present in human breast milk. RPV is present in rat milk and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF [see Data]. It is unknown if TAF is present in animal milk.

It is not known if ODEFSEY affects milk production or has effects on the breastfed infant. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving ODEFSEY.

Data

Animal Data

Rilpivirine: In animals, no studies have been conducted to assess the excretion of rilpivirine directly; however RPV was measured in rat pups which were exposed through the milk of treated dams (dosed up to 400 mg/kg/day).

Tenofovir Alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11 [see Data (8.1)]. Tenofovir was excreted into the milk of lactating monkeys, following a single subcutaneous (30 mg/kg) dose of tenofovir, at concentrations up to approximately 4% of plasma concentration resulting in exposure (AUC) of approximately 20% of plasma exposure.

8.4 Pediatric Use

The efficacy and safety of ODEFSEY as a complete regimen for the treatment of HIV-1 infection was established in pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg [see Dosage and Administration (2.2)]. Use of ODEFSEY in this age group is supported by adequate and well-controlled studies of RPV+FTC+TDF in adults with HIV-1 infection, adequate and well-controlled studies of FTC+TAF with EVG+COBI in adults with HIV-1 infection, and by the following pediatric studies [see Clinical Studies (14)]:

48-week open-label trial of 36 antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years old weighing at least 32 kg treated with 25 mg per day of RPV and other antiretrovirals. The safety and efficacy of RPV and other antiretrovirals was similar to that of antiretroviral treatment-naïve HIV-1 infected adults on this regimen.

24-week open-label trial of 23 antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years old (weighing at least 35 kg) treated with FTC+TAF with EVG+COBI. The safety and efficacy of FTC+TAF with EVG+COBI was similar to that of antiretroviral treatment-naïve HIV-1 infected adults on this regimen.

Because it is a fixed-dose combination tablet, the dose of ODEFSEY cannot be adjusted for patients of lower age and weight. The safety and efficacy of ODEFSEY have not been established in pediatric patients less than 12 years of age or weighing less than 35 kg [see Clinical Pharmacology (12.3)].

8.5 Geriatric Use

In clinical trials, 80 of the 97 subjects enrolled aged 65 years and over received FTC+TAF with EVG+COBI. No differences in safety or efficacy have been observed between elderly subjects and those between 12 and less than 65 years of age. Clinical trials of RPV did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

No data are available on overdose of ODEFSEY in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with ODEFSEY consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient.

Emtricitabine (FTC): Limited clinical experience is available at doses higher than the recommended dosage of FTC in ODEFSEY. In one clinical pharmacology study, single doses of FTC 1200 mg (6 times the dose in ODEFSEY) were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known.

Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether FTC can be removed by peritoneal dialysis.

Rilpivirine (RPV): Human experience of overdose with RPV is limited. There is no specific antidote for overdose with RPV. Since RPV is highly bound to plasma protein, dialysis is unlikely to result in significant removal of RPV.

Administration of activated charcoal may be used to aid in removal of unabsorbed active substance.

Tenofovir Alafenamide (TAF): Limited clinical experience is available at doses higher than the recommended dosage of TAF in ODEFSEY. A single dose of 125 mg TAF (5 times the dose of TAF in ODEFSEY) was administered to 48 healthy subjects; no serious adverse reactions were reported. The effects of higher doses are unknown. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.

Emtricitabine: The chemical name of FTC is 4-amino-5-fluoro-1-(2R-hydroxymethyl-1,3-oxathiolan-5S-yl)-(1H)-pyrimidin-2-one. FTC is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position.

FTC has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24 and has the following structural formula:

FTC is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.

Rilpivirine: The chemical name of rilpivirine hydrochloride drug substance is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C22H18N6 ∙ HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula:

Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

Cardiac Electrophysiology

When higher than recommended RPV doses of 75 mg (3 times the recommended dosage in ODEFSEY) once daily and 300 mg (12 times the recommended dosage in ODEFSEY) once daily were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of RPV 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6 times and 6.7 times, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of RPV [see Warnings and Precautions (5.4)].

The effect of RPV at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo-, and active- (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction was 2 (5) milliseconds (i.e., below the threshold of clinical concern).

In a thorough QT/QTc study in 48 healthy subjects, TAF at the recommended dose and at a dose approximately 5 times the recommended dose, did not affect the QT/QTc interval and did not prolong the PR interval.

The effect of FTC on the QT interval is not known.

12.3 Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic properties of the components of ODEFSEY are provided in Table 4. The multiple dose pharmacokinetic parameters of FTC, RPV and TAF and its metabolite tenofovir are provided in Table 5.

In vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1 in hepatocytes. Upon coadministration with the moderate CYP3A inducer probe efavirenz, TAF exposure was unaffected.

From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection treated with EVG+COBI+FTC+TAF (n=841).

Cmax(microgram per mL)

2.1 (20.2)

NA

0.16 (51.1)

0.02 (26.1)

AUCtau(microgram∙hour per mL)

11.7 (16.6)

2.2 (38.1)

0.21 (71.8)

0.29 (27.4)

Ctrough(microgram per mL)

0.10 (46.7)

0.08 (44.3)

NA

0.01 (28.5)

Specific Populations

Patients with Renal Impairment

Rilpivirine: Population pharmacokinetic analysis indicated that RPV exposure was similar in HIV-1 infected subjects with eGFR 60 to 89 mL per minute by Cockcroft-Gault method relative to HIV-1 infected subjects with normal renal function. There is limited or no information regarding the pharmacokinetics of RPV in patients with moderate or severe renal impairment or in patients with end-stage renal disease [see Use in Specific Populations (8.6)].

Tenofovir Alafenamide: The pharmacokinetics of FTC+TAF with EVG+COBI in HIV-1 infected subjects with renal impairment (eGFR 30 to 69 mL per minute by Cockcroft-Gault method) were evaluated within a subset of virologically-suppressed subjects in an open-label trial (Table 6).

Table 6 Pharmacokinetics of the FTC, TAF, and a Metabolite of TAF (Tenofovir) in HIV-Infected Adults with Renal Impairment as Compared to Subjects with Normal Renal Function

Emtricitabine: The pharmacokinetics of FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited.

Tenofovir Alafenamide: Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolite tenofovir were not observed in subjects with mild, moderate, (Child-Pugh A and B) or severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.7)].

Hepatitis B and/or Hepatitis C Virus Coinfection

The pharmacokinetics of FTC and TAF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus. Population pharmacokinetic analysis indicated that hepatitis B and/or C virus coinfection had no clinically relevant effect on the exposure of RPV.

Pediatric Patients

Exposures of TAF in 24 pediatric subjects with HIV-1 infection aged 12 to less than 18 years who received FTC+TAF with EVG+COBI were decreased (23% for TAF AUC) compared to exposures achieved in treatment-naïve adults following administration of FTC+TAF with EVG+COBI. These exposure differences are not thought to be clinically significant based on exposure-response relationships. FTC exposures were similar in adolescents compared to treatment-naïve adults. The PK of RPV in antiretroviral HIV-1-infected pediatric subjects 12 to less than 18 years of age who received RPV 25 mg once daily were comparable to those in HIV-1 infected adults. As in adults, there was no impact of body weight on RPV PK in pediatric subjects [see Use In Specific Populations (8.4)].

Geriatric Patients

The pharmacokinetics of FTC and TAF have not been fully evaluated in the elderly (65 years of age and older). Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of FTC+TAF with EVG+COBI showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age.

Based on population pharmacokinetic analyses, no dosage adjustment is recommended based on race.

Gender

Based on population pharmacokinetic analyses, no dosage adjustment is recommended based on gender.

Drug Interaction Studies

Rilpivirine: RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV.

RPV at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.

TAF is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1. TAF is a weak inhibitor of CYP3A in vitro. TAF is not an inhibitor or inducer of CYP3A in vivo.

The drug interaction studies described in Tables 7–10 were conducted with ODEFSEY (FTC/RPV/TAF) or the components of ODEFSEY (FTC, RPV, or TAF) administered individually.

The effects of coadministered drugs on the exposures of RPV and TAF are shown in Tables 7 and 8, respectively. The effects of RPV and TAF on the exposure of coadministered drugs are shown in Tables 9 and 10, respectively. For information regarding clinical recommendations, see Drug Interactions (7).

Table 7 Changes in Pharmacokinetic Parameters for RPV in the Presence of Coadministered Drugs in Healthy Subjects

12.4 Microbiology

Mechanism of Action

Emtricitabine: FTC, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Ɛ, and mitochondrial DNA polymerase γ.

Tenofovir Alafenamide: TAF is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain termination.

Tenofovir has activity against human immunodeficiency virus (HIV-1). Cell culture studies have shown that both tenofovir and FTC can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria cell culture.

Antiviral Activity in Cell Culture

Emtricitabine, Rilpivirine, and Tenofovir Alafenamide: The combinations of FTC, RPV, and TAF were not antagonistic with each other in cell culture combination antiviral activity assays. In addition, FTC, RPV, and TAF were not antagonistic with a panel of representatives from the major classes of approved anti-HIV agents (NNRTIs, NRTIs, INSTIs, and PIs).

Emtricitabine: HIV-1 isolates with reduced susceptibility to FTC were selected in cell culture. Reduced susceptibility to FTC was associated with M184V or I substitutions in HIV-1 RT.

Rilpivirine: RPV-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI-resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to RPV included: L100I, K101E, V106I and A, V108I, E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C, and M230I and L.

Tenofovir Alafenamide: HIV-1 isolates with reduced susceptibility to TAF were selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R substitution in HIV-1 RT, sometimes in the presence of S68N or L429I substitutions; in addition, a K70E substitution in HIV-1 RT was observed.

In Clinical Trials

In HIV-1-Infected Subjects With No Antiretroviral Treatment History

Emtricitabine and Tenofovir Alafenamide: The resistance profile of ODEFSEY for the treatment of HIV-1 infection is based on studies of FTC+TAF with EVG+COBI in the treatment of HIV-1 infection. In a pooled analysis of antiretroviral-naïve subjects, genotyping was performed on plasma HIV-1 isolates from all subjects with HIV-1 RNA greater than 400 copies per mL at confirmed virologic failure, at Week 48, or at time of early study drug discontinuation. Genotypic resistance developed in 7 of 14 evaluable subjects. The resistance–associated substitutions that emerged were M184V/I (N=7) and K65R (N=1). Three subjects had virus with emergent R, H, or E at the polymorphic Q207 residue in reverse transcriptase.

Rilpivirine: In the Week 96 pooled resistance analysis for adult subjects receiving RPV or efavirenz in combination with FTC/TDF, the emergence of resistance was greater among subjects' viruses in the RPV+FTC/TDF arm compared to the efavirenz + FTC/TDF arm and was dependent on baseline viral load. In the Week 96 resistance analysis, 14% (77/550) of the subjects in the RPV+FTC/TDF arm and 8% (43/546) of the subjects in the efavirenz + FTC/TDF arm qualified for resistance analysis; 61% (47/77) of the subjects who qualified for resistance analysis (resistance-analysis subjects) in the RPV+FTC/TDF arm had virus with genotypic and/or phenotypic resistance to RPV compared to 42% (18/43) of the resistance-analysis subjects in the efavirenz + FTC/TDF arm who had genotypic and/or phenotypic resistance to efavirenz. Moreover, genotypic and/or phenotypic resistance to emtricitabine or tenofovir emerged in viruses from 57% (44/77) of the resistance-analysis subjects in the RPV arm compared to 26% (11/43) in the efavirenz arm.

Emerging NNRTI substitutions in the RPV resistance analysis of subjects' viruses included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L, and M230L, which were associated with an RPV phenotypic fold change range of 2.6–621. The E138K substitution emerged most frequently during RPV treatment, commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V and NRTI resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F, K219E/R) emerged more frequently in the RPV resistance-analysis subjects than in efavirenz resistance-analysis subjects.

NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline viral loads of less than or equal to 100,000 copies/mL compared to viruses from subjects with baseline viral loads of greater than 100,000 copies/mL: 23% (10/44) compared to 77% (34/44) of NNRTI-resistance substitutions and 20% (9/44) compared to 80% (35/44) of NRTI-resistance substitutions. This difference was also observed for the individual emtricitabine/lamivudine and tenofovir resistance substitutions: 22% (9/41) compared to 78% (32/41) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI and/or NRTI-resistance substitutions emerged less frequently in the resistance analysis of the viruses from subjects with baseline CD4+ cell counts greater than or equal to 200 cells/mm3 compared to the viruses from subjects with baseline CD4+ cell counts less than 200 cells/mm3: 32% (14/44) compared to 68% (30/44) of NNRTI-resistance substitutions and 27% (12/44) compared to 73% (32/44) of NRTI-resistance substitutions.

In Virologically-Suppressed Subjects

Emtricitabine and Tenofovir Alafenamide: One subject was identified with emergent resistance to FTC or TAF (M184M/I) out of 4 virologic failure subjects in a clinical study of virologically-suppressed subjects who switched from a regimen containing FTC+TDF to FTC+TAF with EVG+COBI (N=799).

Rilpivirine: Through Week 48, 4 subjects who switched their protease inhibitor-based regimen to FTC/RPV/TDF (4 of 469 subjects, 0.9%) and 1 subject who maintained their regimen (1 of 159 subjects, 0.6%) developed genotypic and/or phenotypic resistance to a study drug. All 4 of the subjects who had resistance emergence on FTC/RPV/TDF had evidence of FTC resistance and 3 of the subjects had evidence of RPV resistance.

ODEFSEY: Through Week 48, in subjects who switched to ODEFSEY from FTC/RPV/TDF or EFV/FTC/TDF (Trials 1216 (N=316) and 1160 (N=438), respectively), of seven subjects who developed virologic failure, three subjects had detectable NNRTI and/or NRTI resistance substitutions at virologic failure that were pre-existing in the baseline sample by proviral DNA sequencing; one of these subjects resuppressed while maintaining ODEFSEY.

Cross-Resistance

Emtricitabine: FTC-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.

Rilpivirine: Considering all of the available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of RPV: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, M230L, and the combination of L100I+K103N.

Cross-resistance in site-directed mutant virus has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52 times, 15 times, and 12 times decreased susceptibility to RPV, respectively. The combination of E138K and M184I showed 6.7 times reduced susceptibility to RPV compared to 2.8 times for E138K alone. The K103N substitution did not show reduced susceptibility to RPV by itself. However, the combination of K103N and L100I resulted in a 7 times reduced susceptibility to RPV. In another study, the Y188L substitution resulted in a reduced susceptibility to RPV of 9 times for clinical isolates and 6 times for site-directed mutants. Combinations of 2 or 3 NNRTI resistance-associated substitutions gave decreased susceptibility to RPV (fold change range of 3.7–554) in 38% and 66% of mutants, respectively.

Cross-resistance to efavirenz, etravirine, and/or nevirapine is likely after virologic failure and development of RPV resistance.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Emtricitabine: In long-term carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (23 times the human systemic exposure at the recommended dose of 200 mg per day in ODEFSEY) or in rats at doses up to 600 mg per kg per day (28 times the human systemic exposure at the recommended dose in ODEFSEY).

FTC did not affect fertility in male rats at approximately 140 times or in male and female mice at approximately 60 times higher exposures (AUC) than in humans given the recommended 200 mg daily dose in ODEFSEY. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended 200 mg daily dose in ODEFSEY.

Rilpivirine: RPV was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 20, 60, and 160 mg per kg per day were administered to mice and doses of 40, 200, 500, and 1500 mg per kg per day were administered to rats. In rats, there were no drug-related neoplasms. In mice, RPV was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to RPV were 21 times (mice) and 3 times (rats) relative to those observed in humans at the recommended dose (25 mg once daily) in ODEFSEY.

RPV has tested negative in the absence and presence of a metabolic activation system, in the in vitro Ames reverse mutation assay and in vitro clastogenicity mouse lymphoma assay. RPV did not induce chromosomal damage in the in vivo micronucleus test in mice.

In a study conducted in rats, there were no effects on mating or fertility with RPV up to 400 mg per kg per day, a dose of RPV that showed maternal toxicity. This dose is associated with an exposure that is approximately 40 times higher than the exposure in humans at the recommended dose of 25 mg once daily in ODEFSEY.

Tenofovir Alafenamide: Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF administration, carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the recommended dose of TDF (300 mg) for HIV-1 infection. The tenofovir exposure in these studies was approximately 167 times (mice) and 55 times (rat) those observed in humans after administration of the daily recommended dose of ODEFSEY. At the high dose in female mice, liver adenomas were increased at tenofovir exposures approximately 10 times (300 mg TDF) and 167 times (ODEFSEY) the exposure observed in humans. In rats, the study was negative for carcinogenic findings.

There were no effects on fertility, mating performance or early embryonic development when TAF was administered to male rats at a dose equivalent to 62 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 14 days prior to mating through Day 7 of gestation.

13.2 Animal Toxicology and/or Pharmacology

Minimal to slight infiltration of mononuclear cells in the posterior uvea was observed in dogs with similar severity after three- and nine-month administration of TAF; reversibility was seen after a three-month recovery period. No eye toxicity was observed in the dog at systemic exposures of 5 (TAF) and 15 (tenofovir) times the exposure seen in humans at the recommended daily TAF dose in ODEFSEY.

14 CLINICAL STUDIES

In Trial 1216, the efficacy and safety of switching from emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) to ODEFSEY were evaluated in a randomized, double-blind study of virologically-suppressed HIV-1 infected adults. Subjects were suppressed (HIV-1 RNA <50 copies/mL) on their baseline regimen of FTC/RPV/TDF for at least 6 months and have no documented resistance mutations to FTC, TAF, or RPV prior to study entry. Subjects were randomized in a 1:1 ratio to either switch to ODEFSEY (N=316) once daily or stay on FTC/RPV/TDF (N=314) once daily. Subjects had a mean age of 45 years (range: 23–72), 90% were male, 75% were White, and 19% were Black. The mean baseline CD4+ cell count was 709 cells/mm3 (range: 104–2527).

In Trial 1160, the efficacy and safety of switching from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) to ODEFSEY were evaluated in a randomized, double-blind study of virologically-suppressed HIV-1 infected adults. Subjects must have been stably suppressed (HIV-1 RNA <50 copies/mL) on their baseline regimen of EFV/FTC/TDF for at least 6 months and have no documented resistance mutations to FTC, TAF, or RPV prior to study entry. Subjects were randomized in a 1:1 ratio to either switch to ODEFSEY (N=438) once daily or stay on EFV/FTC/TDF (N=437) once daily. Subjects had a mean age of 48 years (range: 19–76), 87% were male, 67% were White, and 27% were Black. The mean baseline CD4+ cell count was 700 cells/mm3 (range: 140–1862).

Treatment outcomes of Trials 1216 and 1160 are presented in Table 11.

Table 11 Virologic Outcomes of Trials 1216 and 1160 at Week 48* in Virologically-Suppressed Subjects who Switched to ODEFSEY

Included subjects who had HIV-1 RNA ≥50 copies/mL in the Week 48 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.

Discontinued Study Drug Due to AE or Death and Last Available HIV-1 RNA <50 copies/mL

2%

1%

3%

1%

Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA <50 copies/mL §

4%

4%

5%

5%

Missing Data During Window but on Study Drug

<1%

1%

1%

1%

14.2 Clinical Trial Results for Subjects with no Antiretroviral Treatment History for Components of ODEFSEY

The efficacy of RPV, FTC, and TAF in the treatment of HIV-1 infection in adults as initial therapy in those with no antiretroviral treatment history [see Indications and Usage (1)] was established in trials of:

RPV+FTC/TDF in HIV-1 infected adults as initial therapy in those with no antiretroviral treatment history (n=550). The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 77% at Week 96. The virologic response rate at 96 weeks was 83% in subjects with baseline HIV-1 RNA less than or equal to 100,000 copies per mL and 71% in subjects with baseline HIV-1 RNA greater than 100,000 copies per mL. Further, the virologic response rate at 96 weeks among subjects with baseline CD4+ cell counts less than 200 and greater than or equal to 200 cells/mm3 were 68% and 82%, respectively.

FTC+TAF with EVG+COBI in HIV-1 infected adults as initial therapy in those with no antiretroviral treatment history (n=866). The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 92% at Week 48.

The efficacy of RPV, FTC, and TAF in the treatment of HIV-1 infection in pediatric patients aged 12 to less than 18 years old and greater than 32–35 kg as initial therapy in those with no antiretroviral treatment history and to replace a stable antiretroviral regimen in those who are virologically-suppressed [see Indications and Usage (1)] was established in trials of antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years old with:

RPV in combination with other antiretroviral agents in 36 treatment-naïve HIV-1 infected adolescents weighing at least 32 kg. The majority of subjects (24/36) received RPV in combination with FTC and TDF. Of these 24 subjects, 20 had a baseline HIV-1 RNA less than or equal to 100,000 copies per mL. The virologic response rate in these 20 subjects (i.e., HIV-1 RNA less than 50 copies per mL) was 80% (16/20) at 48 weeks.

FTC+TAF with EVG+COBI in 23 adolescents weighing at least 35 kg. The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 91% at 24 weeks.

In the clinical trial of 248 HIV-1 infected adult patients with estimated creatinine clearance greater than 30 mL per minute but less than 70 mL per minute, 95% (235/248) of the combined populations of treatment-naïve (N=6) begun on FTC+TAF with EVG+COBI and those previously virologically-suppressed on other regimens (N=242) and switched to FTC+TAF with EVG +COBI had HIV-RNA levels less than 50 copies per mL at Week 24.

16 HOW SUPPLIED/STORAGE AND HANDLING

ODEFSEY tablets are gray, capsule-shaped, and film coated with "GSI" debossed on one side and "255" on the other side. Each bottle contains 30 tablets (NDC 61958-2101-1), a silica gel desiccant, and a polyester coil, and is closed with a child-resistant closure.

Store below 30 °C (86 °F).

Keep container tightly closed.

Dispense only in original container.

17 PATIENT COUNSELING INFORMATION

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, and may likewise occur with discontinuation of ODEFSEY [see Warnings and Precautions (5.1)]. Advise the patient to not discontinue ODEFSEY without first informing their healthcare provider.

Severe Skin Reactions and Hypersensitivity

Inform patients that skin reactions ranging from mild to severe, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported with RPV-containing products. Instruct patients to immediately stop taking ODEFSEY and seek medical attention if they develop a rash associated with any of the following symptoms: fever, blisters, mucosal involvement, eye inflammation (conjunctivitis), severe allergic reaction causing swelling of the face, eyes, lips, mouth, tongue or throat which may lead to difficulty swallowing or breathing, and any signs and symptoms of liver problems, as they may be a sign of a more serious reaction. Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be performed and appropriate therapy will be initiated [see Warnings and Precautions (5.2)].

Inform patients that hepatotoxicity has been reported with RPV, therefore, it is important to inform the healthcare professional if patients have underlying hepatitis B or C or elevations in liver-associated tests prior to treatment [see Dosage and Administration (2.1) and Warnings and Precautions (5.6)].

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.7)].

New Onset or Worsening Renal Impairment

Advise patients to avoid taking ODEFSEY with concurrent or recent use of nephrotoxic agents. Renal impairment, including cases of acute renal failure, has been reported in association with the use of tenofovir prodrugs [see Warnings and Precautions (5.8)].

Lactic Acidosis and Severe Hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to ODEFSEY. Advise patients to stop taking ODEFSEY if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.9)].

Missed Dosage

Inform patients that it is important to take ODEFSEY on a regular dosing schedule with a meal and to avoid missing doses, as it can result in development of resistance [see Dosage and Administration (2.2)].

Pregnancy Registry

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to ODEFSEY [see Use in Specific Populations (8.1)].

Worsening of Hepatitis B virus infection. ODEFSEY is not for use to treat chronic hepatitis B virus (HBV) infection. If you have hepatitis B virus (HBV) infection and take ODEFSEY, your HBV may get worse (flare-up) if you stop taking ODEFSEY. A "flare-up" is when your HBV infection suddenly returns in a worse way than before.

Do not run out of ODEFSEY. Refill your prescription or talk to your healthcare provider before your ODEFSEY is all gone.

Do not stop taking ODEFSEY without first talking to your healthcare provider.

If you stop taking ODEFSEY, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking ODEFSEY.

St. John's wort (Hypericum perforatum) or a product that contains St. John's wort

What should I tell my healthcare provider before taking ODEFSEY?

Before taking ODEFSEY, tell your healthcare provider about all your medical conditions, including if you:

have liver problems, including hepatitis B or C virus infection

have kidney problems

have a history of depression or suicidal thoughts

are pregnant or plan to become pregnant. It is not known if ODEFSEY can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with ODEFSEY.Pregnancy Registry: There is a pregnancy registry for women who take ODEFSEY during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.

are breastfeeding or plan to breastfeed. Do not breastfeed if you take ODEFSEY.

You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.

At least one of the medicines in ODEFSEY can pass to your baby in your breast milk. It is not known if the other medicines in ODEFSEY can pass into your breast milk.

Talk with your healthcare provider about the best way to feed your baby during treatment with ODEFSEY.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Some medicines may interact with ODEFSEY. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

You can ask your healthcare provider or pharmacist for a list of medicines that interact with ODEFSEY.

Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take ODEFSEY with other medicines.

How should I take ODEFSEY?

Take ODEFSEY exactly as your healthcare provider tells you to take it. ODEFSEY is taken by itself (not with other HIV-1 medicines) to treat HIV-1 infection.

Take ODEFSEY 1 time each day with a meal.

Do not change your dose or stop taking ODEFSEY without first talking with your healthcare provider. Stay under a healthcare provider's care during treatment with ODEFSEY.

Do not miss a dose of ODEFSEY.

If you take too much ODEFSEY, call your healthcare provider or go to the nearest hospital emergency room right away.

When your ODEFSEY supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to ODEFSEY and become harder to treat.

Severe skin rash and allergic reactions. Skin rash is a common side effect of ODEFSEY. Rash can be serious. Call your healthcare provider right away if you get a rash. In some cases, rash and allergic reaction may need to be treated in a hospital.If you get a rash with any of the following symptoms, stop taking ODEFSEY and call your healthcare provider or get medical help right away:

fever

skin blisters

mouth sores

redness or swelling of the eyes (conjunctivitis)

swelling of the face, lips, mouth, or throat

trouble breathing or swallowing

pain on the right side of the stomach (abdominal) area

dark "tea colored" urine

Depression or mood changes. Tell your healthcare provider right away if you have any of the following symptoms:

feel sad or hopeless

feel anxious or restless

have thoughts of hurting yourself (suicide) or have tried to hurt yourself

Change in liver enzymes. People with a history of hepatitis B or C virus infection or who have certain liver enzyme changes may have an increased risk of developing new or worsening liver problems during treatment with ODEFSEY. Liver problems can also happen during treatment with ODEFSEY in people without a history of liver disease. Your healthcare provider may need to do tests to check your liver enzymes before and during treatment with ODEFSEY.

Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine.

New or worse kidney problems, including kidney failure. Your healthcare provider should do blood and urine tests to check your kidneys before you start and during treatment with ODEFSEY. Your healthcare provider may tell you to stop taking ODEFSEY if you develop new or worse kidney problems.

Too much lactic acid in your blood (lactic acidosis). Too much lactic acid is a serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you get these symptoms: weakness or being more tired than usual, unusual muscle pain, being short of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or a fast or abnormal heartbeat.

Severe liver problems. In rare cases, severe liver problems can happen that can lead to death. Tell your healthcare provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark "tea-colored" urine, light-colored stools, loss of appetite for several days or longer, nausea, or stomach-area pain.

The most common side effects of ODEFSEY are headache and problems sleeping.

These are not all the possible side effects of ODEFSEY.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ODEFSEY?

Store ODEFSEY below 86°F (30°C).

Keep ODEFSEY in its original container.

Keep the container tightly closed.

Keep ODEFSEY and all medicines out of reach of children.

General information about the safe and effective use of ODEFSEY.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ODEFSEY for a condition for which it was not prescribed. Do not give ODEFSEY to other people, even if they have the same symptoms you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about ODEFSEY that is written for health professionals.